Pemetrexed in Advanced Colorectal Cancer

Pemetrexed in Advanced Colorectal Cancer

ABSTRACT: Pemetrexed (Alimta) shows single-agent activity in advanced
colorectal cancer. In two phase II studies in which patients received
pemetrexed at 600 mg/m2 or 500 mg/m2 as first-line treatment for metastatic
disease, objective response rates were 15.4% and 17.2%. These
trials were conducted prior to supplementation with folic acid and vitamin
B12, which markedly decreased the frequency of hematologic toxicities
of pemetrexed; routine supplementation is now included in all
clinical trials of the agent. The marked improvement in toxicity and
tolerance with vitamin supplementation suggests the need to reexamine
optimal dosing in pemetrexed combination schedules. In a National
Surgical Adjuvant Breast and Bowel Project phase II trial in 54 patients
with previously untreated advanced colorectal cancer, pemetrexed
at 500 mg/m2 plus oxaliplatin (Eloxatin) at 120 mg/m2 every 21 days
with folic acid/vitamin B12 supplementation resulted in an objective response
of 23%. Three additional patients (5.6%) had unconfirmed partial
response (partial response at one visit), and 27 patients (50%) had
stable disease. Median progression-free survival was 5.3 months and
median duration of response was 5.7 months; median overall survival
was approximately 11.05 months. Grade 3/4 neutropenia was observed
in only 17% of patients and treatment was well tolerated. A phase I/II
study is under way to identify and assess the optimal combination of
pemetrexed/irinotecan in second-line treatment of advanced colorectal
cancer. Planned studies include a phase I study examining the combination
of pemetrexed and oxaliplatin given every 2 weeks as first-line
treatment, and a phase I/II trial to identify the optimal pemetrexed/
oxaliplatin dose in a 21-day schedule and to compare pemetrexed/
oxaliplatin with FOLFOX4 in first-line treatment of metastatic disease.
All of these trials include vitamin supplementation. A phase III trial
comparing the every-3-week pemetrexed/oxaliplatin regimen with
FOLFOX4 as first-line treatment will be initiated if the outcome of the
phase II trial is encouraging.

Pemetrexed (Alimta) is a multitargeted
antifolate agent that
inhibits several enzymes in
pyrimidine and purine biosynthesis
pathways, including thymidylate synthase
(TS), dihydrofolate reductase
(DHFR), and glycinamide ribonucleotide
formyltransferase (GRFT).[1,2]
Pemetrexed exhibits single-agent activity
against a number of solid tumors,
including non-small-cell lung
cancer, mesothelioma, and pancreas,
colorectal, gastric, bladder, breast, and
head and neck cancers.[2]
The characteristic toxicities of antifolate
agents are well recognized, with
the primary toxicity being myelosuppression.
In early studies of pemetrexed
performed without folic acid/
vitamin B12 supplementation, the primary
toxicities of pemetrexed were
myelosuppression, skin rash, and mucositis,
with neutropenia being the primary
dose-limiting toxicity. Analysis
of data from patients in pemetrexed
phase II studies performed without vitamin
supplementation showed a highly
significant association of myelosuppression
with elevated plasma levels of
homocysteine (> 12 mM)-a sensitive
marker for reduced functional availability
of folate or vitamin B12.[3]
Supplementation with folic acid
and vitamin B12 is now routinely included
in pemetrexed treatment in clinical trials. As shown in Table 1,
routine supplementation markedly reduces
rates of severe hematologic and
nonhematologic toxicities.[4] Pemetrexed
exhibits good single-agent activity
in metastatic colorectal cancer
and is being evaluated in combination
with oxaliplatin (Eloxatin) and
irinotecan (Camptosar) in this setting.
The improved toxicity and tolerability
of pemetrexed with vitamin supplementation
raises the possibility of
delivering higher doses than those suggested
by phase I studies performed
without supplementation.
Single-Agent Pemetrexed in
Metastatic Colorectal Cancer
Pemetrexed has been evaluated in
two phase II studies in patients with
advanced colorectal cancer.[5,6] In
both studies, no prior chemotherapy
for metastatic disease was permitted,
and adjuvant therapy had to have been
completed more than 12 months prior
to study entry. No vitamin supplementation
was used in either trial.
John et al reported data from a US
multicenter trial in which 46 patients
(27 male) with a median age of 59
years (range: 33 to 86 years) received
pemetrexed at 600 mg/m2 via 10-minute
intravenous (IV) infusion every 3
weeks.[5] Eastern Cooperative Oncology
Group (ECOG) performance status
(PS) was 0 in 28 patients, 1 in 11,
and 2 in 1, with status unknown in 6.
Fifteen patients had received prior adjuvant
chemotherapy and eight had received
prior radiation therapy.
Among 39 patients evaluable for
response, complete response was observed
in one patient and partial response
was observed in five, yielding
a response rate of 15.4%. Median survival
was 16.2 months, and median
time to disease progression was 4.4
months. Among 41 patients evaluable
for toxicity, hematologic toxicity was
the most common toxicity, with grade
3/4 neutropenia occurring in 56% of
patients (Table 2).
In a Canadian multicenter trial of
Cripps et al, 33 patients (17 female)
with a median age of 68 years (range:
45 to 77 years) received pemetrexed
at 600 mg/m2 via 10-minute infusion
every 3 weeks, or at 500 mg/m2 following
a decision to reduce the study
dose.[6] ECOG performance status
was 0 in 13 patients, 1 in 18, and 2 in
2. Nine patients had received prior
adjuvant therapy and 3 had received
prior radiation therapy.
Among 29 patients evaluable for
response, complete response occurred
in 1 patient and partial response occurred
in 4, yielding a response rate
of 17.2%. Median survival was 15.1
months, and median time to disease
progression was 3.3 months. Among
the 33 patients evaluable for toxicity,
hematologic toxicity was the most common
toxicity (Table 2). Grade 3/4 neutropenia
occurred in 56% of patients at
the 600-mg/m2 dose and in 48% at the
500-mg/m2 dose. Dosing at 500 mg/m2
was associated with marked reductions
in rates of grade 3/4 thrombocytopenia
(4% vs 33%) and anemia (9% vs 22%).
Figure 1(A) shows a comparison
of response rates with pemetrexed in
these phase II studies with response
rates observed in relevant phase II
and/or phase III studies with other
single-agent regimens with activity in
metastatic colorectal cancer (presented
as a cumulative total for comparison).
The comparative data suggest
that responses with pemetrexed are
similar to those with other bolus TS
inhibitors. Figure 1(B) compares selected
grade 3/4 toxicity rates in phase
II studies of pemetrexed in various
settings that have included routine vitamin
supplementation with toxicity
rates reported for the other regimens
in phase II and III studies in metastatic
colorectal cancer. Pemetrexed treatment
with routine vitamin supplementation
is associated with an approximately
10% rate of grade 3/4
neutropenia, and rates of mucositis,
diarrhea, and hand-foot syndrome are
lower than or similar to rates observed
with the other regimens.
Pemetrexed Plus Oxaliplatin
Both pemetrexed and oxaliplatin
have shown clinical activity as single
agents in colorectal cancer. The finding
of synergistic antitumor effects with
the combination in preclinical models,
and the different mechanisms of action
and toxicity patterns of the two agents
make pemetrexed/oxaliplatin an attractive
combination regimen.
Raymond et al evaluated the antiproliferative
potential of pemetrexed
combined with drugs with known therapeutic
activity against colorectal
cancer (ie, fluorouracil [5-FU], oxaliplatin,
and the active metabolite of
irinotecan SN38).[7] The activity of
single-agent pemetrexed or combinations
with one the three agents was
assessed in parental human HT29 colorectal
cancer lines and in 5-FU-resistant
HT29-5FU cells, with either
simultaneous or sequential administration.
(Median-effect plot analysis
expressed the possible functional interaction
between the agents.)
Figure 2 shows results of simultaneous
or sequential exposure of human
HT29 and 5-FU-resistant HT29
colorectal cancer tumor cells to pemetrexed
and oxaliplatin. Results show
clear synergy, indicated by a combination
index < 1, when the drugs are
administered together. The drug combinations
and sequence with optimal
effects were also evaluated in athymic
mice bearing human HT29 tumor
cell xenografts. Figure 3 illustrates
results using the agents alone
or in combination compared with controls
in human HT29 xenografts, indicating
a superior effect in delaying
tumor growth with the combination.
Misset et al conducted a phase I
study (without vitamin supplementation)
in 36 patients with metastatic
solid tumors who received pemetrexed
at an initial dose of 300 mg/m2
by 10-minute infusion followed by
oxaliplatin at an initial dose of 85
mg/m2 via 2-hour infusion on day 1
every 21 days.[8] The combination
was given at six dose levels up to
pemetrexed at 500 mg/m2 and oxaliplatin
at 130 mg/m2. Of 45 patients
enrolled, 36 were evaluable for toxicity
and response.
Dose-limiting toxicities occurred
in 5 patients out of 16 at the pemetrexed
at 500 mg/m2 plus oxaliplatin
at 130 mg/m2 dose level, with the
dose-limiting toxicities consisting of
grade 3/4 diarrhea in two patients,
grade 3/4 febrile neutropenia in two,
grade 3 paresthesias in one; there was
one toxic death. The maximum tolerated
dose was thought to be pemetrexed
at 500 mg/m2 and oxaliplatin at
130 mg/m2. Five responses (all partial)
were reported over a broad range
of solid tumors. The recommended
regimen without vitamins for phase II
studies was pemetrexed at 500 mg/m2
plus oxaliplatin at 120 mg/m2.
In a phase II trial performed by
Atkins et al and the National Surgical
Adjuvant Breast and Bowel Project
(NSABP) foundation research program,
54 patients with previously
untreated stage IV colorectal cancer
were treated with pemetrexed at 500
mg/m2 plus oxaliplatin at 120 mg/m2
every 21 days with folic acid/vitamin
B12 supplementation throughout the
course of study treatment.[9] In the absence
of progressive disease, treatment
was to continue for at least six cycles,
and could be continued at the discretion
of the investigator until disease
progression or unacceptable toxicity
occurred.
Patients had a median age of 60
years (range: 33 to 80 years), 30
(55.6%) were male, and 45 (83.3%)
had colon cancer and 9 (16.7%) had
rectal cancer. ECOG PS was 0 in 30
patients (55.6%) and 1 or 2 in 24
(44.4%). Two patients (3.7%) had received
prior radiation therapy and 16
(29.6%) had received prior chemotherapy.
(However, no prior chemotherapy
for advanced disease and no
adjuvant chemotherapy within 6
months were allowed.) Tumor sites
consisted of the liver alone in 22 patients
(40.7%), the liver and an additional
site in 22 (40.7%), and other
sites in 10 (18.5%). Patients received
a median of six treatment cycles
(mean: 6.35 cycles).
A total of 54 patients were evaluable
for toxicity and 47 for response.
The confirmed objective response rate
was 23% (Table 3). Three additional
patients (5.6%) had unconfirmed partial
response (partial response at one
visit); 27 patients (50%) had stable disease.
Early death occurred in one patient,
who died unexpectedly at home
after the first treatment cycle. Median
progression-free survival was 5.3
months and median duration of response
was 5.7 months. Overall survival
was approximately 11.05 months.
Table 4 shows rates of grade 1/2
and grade 3/4 diarrhea, neutropenia,
neutropenic complications, cutaneous
toxicity, mucositis, neurologic toxicity,
and pharyngeal/laryngeal dyses-
thesias in this trial and reported rates
of these toxicities from phase III trials
of the IFL (irinotecan plus 5-FU/leucovorin)
regimen [10] and the FOLFOX4
(oxaliplatin plus 5-FU/
leucovorin) regimen reported by de
Gramont and colleagues[11] in advanced
colorectal cancer.
Also included in Table 4 for comparison
are grade 3/4 toxicities rates
from the NSABP N9741 phase III
trial of Goldberg et al, who compared
IFL, FOLFOX4, and irinotecan/oxaliplatin
(IROX) as first-line treatment
in patients with advanced disease.[12]
As can be seen, the pemetrexed/oxaliplatin
combination with vitamin
supplementation resulted in no grade
3/4 diarrhea and a notably low rate of
grade 3/4 neutropenia. Other grade 3/
4 toxicities consisted of fatigue
(13.0%), thrombocytopenia (11.1%),
hyperglycemia (11.1%), nausea
(9.3%), anemia (7.5%), thrombosis/
embolism (5.6%), vomiting (3.7%),
and allergic reactions (1.9%). These
findings suggest the potential for using
higher doses of pemetrexed in
combination with oxaliplatin when
routine vitamin supplementation is
provided, with the possibility of optimizing
therapeutic response.
Pemetrexed Plus Irinotecan
In a phase I trial of the combination
of pemetrexed and irinotecan performed
without vitamin supplementation,
pemetrexed was given via
10-minute infusion at an initial dose
of 300 mg/m2 on day 1 and irinotecan
was given via 90-minute infusion at
an initial dose of 175 mg/m2 on day 1
every 21 days. The dose suggested
for phase II study in patients with
advanced or metastatic colorectal cancer
was pemetrexed at 400 mg/m2 and
irinotecan at 250 mg/m2.[13,14]
Kroening et al further conducted a
phase I dose-escalation trial (of the
phase II amendment) in 12 patients in
the second-line setting (with vitamin
supplementation). The authors reported
that the combination of pemetrexed
at 500 mg/m2 plus irinotecan at 300
mg/m2 was well tolerated and selected
for a phase II trial in second-line colorectal
cancer in patients with locally
advanced or metastatic disease.[14]
However, given the findings on
improved toxicity with vitamin supplementation,
a new phase I/II study
has been undertaken. This US and
European multicenter trial is enrolling
patients who have had one prior
course of chemotherapy for metastatic
colorectal cancer but no prior exposure
to irinotecan. All patients are
to receive folic acid and vitamin B12
supplementation. The initial dose in
the phase I portion of the study is
pemetrexed at 300 mg/m2 plus irinotecan
at 175 mg/m2 on day 1 every 3
weeks. Thus far, minimal toxicity has
been observed in the first 20 patients
enrolled.
Conclusion
Pemetrexed is active as a single
agent in first-line treatment of advanced
colorectal cancer. Administration
of folic acid and vitamin B12
with pemetrexed markedly reduces
hematologic and other toxicities; all
trials of pemetrexed now include routine
vitamin supplementation. Pemetrexed
has a convenient administration
schedule and can be safely administered
in combination with a full single-
agent dose of oxaliplatin. The
pemetrexed/oxaliplatin combination is
active and well tolerated in patients
with metastatic colorectal cancer. Ongoing
and planned studies will help
determine optimal schedules for pemetrexed
in combination with oxaliplatin
and irinotecan.
In addition to the ongoing phase I/
II study of pemetrexed/irinotecan in
second-line treatment, a phase I study
is planned to examine the combination
of pemetrexed and oxaliplatin given
every 2 weeks as first-line
treatment, and a phase I/II trial is
planned to identify the optimal pemetrexed/
oxaliplatin dose in a 21-day
schedule with vitamin supplementation
and to compare pemetrexed/oxaliplatin
with FOLFOX4 in
randomized fashion in first-line treatment
of metastatic disease. Pending
the outcome of the randomized phase
II portion of the latter trial is the initiation
of a planned phase III trial comparing
the 3-week pemetrexed/
oxaliplatin regimen with FOLFOX4
as first-line treatment.

Disclosures

The authors have no
significant financial interest or other relationship
with the manufacturers of any products
or providers of any service mentioned in this
article.